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Changes in Expression of Class 3 Semaphorins and Their Receptors During Development of the Rat Retina and Superior Colliculus

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Changes in Expression of Class 3 Semaphorins and Their Receptors During Development of the Rat Retina and Superior Colliculus Sharma et al. BMC Developmental Biology 2014, 14:34 http://www.biomedcentral.com/1471-213X/14/34 RESEARCH ARTICLE Open Access Changes in expression of Class 3 Semaphorins and their receptors during development of the rat retina and superior colliculus Anil Sharma1*, Chrisna J LeVaillant1, Giles W Plant1,2 and Alan R Harvey1 Abstract Background: Members of the Semaphorin 3 family (Sema3s) influence the development of the central nervous system, and some are implicated in regulating aspects of visual system development. However, we lack information about the timing of expression of the Sema3s with respect to different developmental epochs in the mammalian visual system. In this time-course study in the rat, we document for the first time changes in the expression of RNAs for the majority of Class 3 Semaphorins (Sema3s) and their receptor components during the development of the rat retina and superior colliculus (SC). Results: During retinal development, transcript levels changed for all of the Sema3s examined, as well as Nrp2, Plxna2, Plxna3, and Plxna4a. In the SC there were also changes in transcript levels for all Sema3s tested, as well as Nrp1, Nrp2, Plxna1, Plxna2, Plxna3, and Plxna4a. These changes correlate with well-established epochs, and our data suggest that the Sema3s could influence retinal ganglion cell (RGC) apoptosis, patterning and connectivity in the maturing retina and SC, and perhaps guidance of RGC and cortical axons in the SC. Functionally we found that SEMA3A, SEMA3C, SEMA3E, and SEMA3F proteins collapsed purified postnatal day 1 RGC growth cones in vitro. Significantly this is a developmental stage when RGCs are growing into and within the SC and are exposed to Sema3 ligands. Conclusion: These new data describing the overall temporal regulation of Sema3 expression in the rat retina and SC provide a platform for further work characterising the functional impact of these proteins on the development and maturation of mammalian visual pathways. Keywords: Retinal ganglion cells, Collapse assay, qPCR, Neuropilins, Plexins, Cell adhesion molecules Background of visual pathways in mammals. It is likely then that other The mammalian visual system is complex, and the de- molecules are also involved during the development and velopmental events that give rise to this highly organised maturation of the mammalian visual system, and in this system are similarly complex and exquisitely ordered. context recent attention has turned to the Semaphorins. The timing of the major developmental events of the Semaphorins (Semas) have been implicated in neural mammalian visual system has been well characterised, and vascular aspects of visual system development in and many of the molecular cues controlling these critical various species including frog [8,9], zebrafish [10-14], events have been elucidated (for example Ephs/Ephrins, goldfish [15], and chicken [16-21]. In mouse the mem- Slits/Robo, Netrin/DCC, and various neurotrophic factors brane bound Class 5 and Class 6 Semaphorins are in- [1-7]). However despite our increased knowledge about volved in lamination of the retina [22-24], and guidance these molecular cues, they are not sufficient to explain of retinal ganglion cell (RGC) axons [25] via contact- completely the complexity and timing of the development mediated interactions. However many previously discov- ered molecular cues in the mammalian visual system are * Correspondence: [email protected] diffusible, and the only vertebrate secreted members of 1School of Anatomy, Physiology and Human Biology, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia the Semaphorins are the Class 3 Semaphorins (Sema3s) Full list of author information is available at the end of the article [26] which are known to be expressed in the developing © 2014 Sharma et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sharma et al. BMC Developmental Biology 2014, 14:34 Page 2 of 14 http://www.biomedcentral.com/1471-213X/14/34 rat retina [27]. It is possible then that the Sema3s also Changes in Class 3 Semaphorins and their receptor influence the complexity and timing of the developing components during rat retinal development mammalian visual system. Expression levels in the retina could be separated into three The Sema3s consist of Sema3a through Sema3g qualitative groups: relatively high expression of Sema3f and [16,26,28-36] and their main receptors are the Neuropilins Plxna2; moderate expression of Nrp1 and Plxna1;andrela- which form multimeric receptor complexes with Plexins tively low expression of the rest (Figures 2, and 3). There and cell adhesion molecules [37]. Sema3s were initially dis- were statistically significant changes in the level of expres- covered as axon guidance molecules [30,38], but are now sion of all Sema3 RNAs in the retina, while of the receptors known to also mediate apoptosis, cell migration, immune only Nrp2, Plxna2, Plxna3,andPlxna4a showed statisti- response, organogenesis, tumour suppression and promo- cally significant changes (Figures 2, and 3; Additional file 1: tion, and vasculature development [39-44]. Sema3s affect at Table S1). least some aspects of the development of the visual system Relative to other time points, Sema3a transcript ex- of rodents [45,46], from where much of our knowledge of pression levels were significantly increased at P14 and in molecular and activity-driven influences on mammalian the adult. Similar to Sema3a, Sema3b transcript expres- visual system development has come [6,47]. sion was relatively stable during retinal development In summary, while we understand much about the until P14, at which time there was increased expression timing of developmental events in the mammalian visual that was maintained into adulthood. Sema3c RNA ex- system, investigation of a potential role for the Sema3s pression was also relatively steady through to P0, in- in these events would benefit from knowledge about the creasing significantly through to P21, and remaining at timing of expression of Sema3s and their receptors dur- that level into the adult. Sema3e RNA levels appeared to ing visual system maturation. We sought to address this increase gradually with retinal maturation and were sig- gap in our knowledge by building on a previous study nificantly higher than E16-P7 levels at P21 and in adult from our laboratory [27], focusing on Sema3s known to rats. Sema3f transcription was temporarily greater at P0 be expressed in RGCs and extending the work to include and then increased again at P21 and beyond. Nrp2 RNA a greater number of receptors as well as analysis of a expression gradually increased throughout retina matur- major central target for those RGCs, the superior collicu- ation, levels at P7 and beyond being significantly greater lus (SC). To that end, we quantified transcript expression than in embryos. Plxna2 and Plxna3 showed nearly in the rat retina and SC over a range of embryonic (E) and identical patterns of altered transcript expression during postnatal (P) developmental time points (E16, E19, birth – development, both peaking significantly at the time of P0, P7, P14, P21 and adult) which were chosen to corres- birth (P0). Plxna4a RNA levels peaked later at P7, but pond to previously established developmental epochs such also again in the adult. as the timing of cell birth, migration, naturally occurring Many of the significant peaks in transcript expression cell death, axonal and dendritic growth, and synaptogene- occurred after the main developmental epochs. However, sis (Figure 1). We also investigated the hypothesis that the changes that were quantified in the retina before P21 Sema3 ligands in the SC can influence RGC axon guid- occurred during periods of RGC apoptosis, and synapse ance using an in vitro growth cone collapse assay on iso- generation and maturation. lated RGCs from a developmental stage when they would be growing into and within the SC in vivo. Changes in Class 3 Semaphorins and their receptor components during development of the rat superior Results colliculus Developmental expression profiles for the Sema3s and There were four qualitative groups of transcript expression their receptors are presented in Figures 2, 3, 4 and 5, levels in the SC: Plxna1 having the highest; followed by with those showing statistically significant changes in Sema3f, Nrp1,andNrp2;thenSema3b, Sema3c and Plxna3; expression explored further. Statistical comparisons il- and lower amounts for the remainder (Figures 4, and 5). lustrated in Figures 2, 3, 4 and 5 are summaries of sta- With the exception of L1cam, all genes of interest changed tistically significant peaks in expression; the entirety of expression significantlyduringSCmaturation. statistical comparisons can be found in Additional file 1: Sema3a RNA levels were highly variable at E16 (149% Table S1. Plxna3 in situ hybridisations at P1 and P7 are coefficient of variance; CV), peaked at E19, and a decline presented in Figure 6 showing co-expression in βIII- with increasing postnatal age. The expression profile of tubulin positive cells (presumptive RGCs). The effects of Sema3b differed from other transcripts; there was large exogenous recombinant Sema3s on RGC growth cone biological variation at many time points, with CVs greater collapse are presented in Figure 7, and data detailing ex- than 100%, and four apparent peaks in expression, only pression and detection of those recombinant Sema3s are one of which reached significance (E19). Sema3c tran- presented in Additional file 2: Figure S1. script expression peaked at E19 and P0, before falling to Sharma et al. BMC Developmental Biology 2014, 14:34 Page 3 of 14 http://www.biomedcentral.com/1471-213X/14/34 Figure 1 Developmental epochs in the rat neural retina and superior colliculus.
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